The ability of the immune system to discriminate between self and non- self is acquired in the thymus during T cell maturation. Self-reactive clones specific for antigens expressed intrathymically are eliminated inside that organ. T cells which can recognize self-antigens not represented intrathymically are not deleted and represent a potential danger. However, such cells are usually rendered tolerant when they recognize their target antigens in the periphery. Autoimmunity may be secondary to a failure of intra-thymic deletion of autoreactive T cells, to a failure to induce peripheral tolerance, or to a breaking of established immunological tolerance. We have concentrated our studies on an analysis of the pathogenesis of several different autoimmune states: 1) Thymectomy of 3 day old mice induces organ-specific autoimmune disease which is characterized by the presence of autoantibodies and T cell infiltrates in the affected organs. Lymph nodes of 3-4 day old mice contain a significant number of thymus-derived CD4+CD8+ T cells that are phenotypically immature, but are enriched in precursors of autoreactive cells. These cells exhibit enhanced reactivity in the syngeneic mixed leukocyte reaction and may be responsible for the initiation of autoimmune disease in the target organs. 2) To understand the factors that regulate immunologic tolerance, we have developed an in vivo model for the superantigen-specific priming of IL-4 producing (Th2) T cells by the injection of mice with superantigen and IL-4. High doses of superantigen were able to induce tolerance in both the naive precursors of IL-4 producing T cells and in T cells already primed for IL-4 production. These studies demonstrate that the IL-4 pathway is susceptible to tolerance induction in vivo and suggest that antigen- specific therapies to inhibit IL-4 production in allergic disease states are feasible. 3) Our ability to prime superantigen specific T cells in the presence of IL-4 raised the possibility that autoantigen specific T cells could also be primed for IL-4 production and could prevent the tissue damaging effects of autoreactive interferon-gamma producing Th1 cells. The administration of IL-4 to animals with experimental allergic encephalomyelitis resulted in amelioration of clinical disease, the induction of antigen-specific IL-4 producing cells, diminished demyelination, and inhibition of the synthesis of inflammatory cytokines in the central nervous system. Modulation of an immune response from one dominated by excessive activity of Th1-like T cells to one dominated by the protective cytokines produced by Th2 T cells may have applicability to the therapy of certain human autoimmune diseases.